Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice

Familial hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere and may lead to hypertrophic, dilated, restrictive, and/or arrhythmogenic cardiomyopathy, 38 congestive heart failure, or sudden cardiac death. We hypothesized that hearts from 39 transgenic HCM mice harboring a mutant myosin heavy chain, increases the energetic 40 cost of contraction in a sex-specific manner. To do this, we assessed Ca2+-sensitivity of 41 42 43 tension and crossbridge kinetics in de-membranated cardiac trabeculae from male and female wild-type (WT) and HCM hearts at an early timepoint (2 months of age). We found a significant effect of sex on Ca2+-sensitivity such that male, but not female, HCM 44 mice displayed a decrease in compared to WT counterparts. The HCM transgene and 45 sex significantly impacted the rate of force redevelopment by a rapid release-restretch 46 protocol and tension cost by the ATPase-tension relationship. In each of these 47 measures, HCM male trabeculae displayed a gain-of-function when compared to WT 48 counterparts. In addition, cardiac remodeling measured by echocardiography, histology, 49 morphometry, and post-translational modifications demonstrated sex- and HCM-specific 50 effects. In conclusion, female and male HCM mice display sex dimorphic crossbridge 51 kinetics that is accompanied by a sex- and HCM-dependent cardiac remodeling at the 52 morphometric, histological and cellular level. 53